Misfolding and aggregation of amyloid proteins into fibrillar aggregates is a central pathogenic event in neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD). Currently, there is a lack of reliable sensors for detecting the range of protein aggregates involved in disease etiology, particularly the prefibrillar aggregate conformations that are more neurotoxic. In this study, the fluorescent sensing of two novel oligomeric p-phenylene ethynylenes (OPEs), anionic OPE1– and cationic OPE2+, for detecting prefibrillar and fibrillar aggregates of AD-associated amyloid-β (Aβ40 and Aβ42) and PD-associated α-synuclein proteins (wildtype, and single mutants A30P, E35K, and A53T) over their monomeric counterparts, were tested. Furthermore, the performance of OPEs was evaluated and compared to thioflavin T (ThT), the most widely used fibril dye. Our results show that OPE1– and OPE2+ exhibited aggregate-specific binding inducing large fluorescence turn-on and spectral shifts based on a combination of backbone planarization, hydrophobic unquenching, and superluminescent OPE complex formation sensing modes. OPEs exhibited higher selectivity, higher binding affinity, and comparable limits of detection for Aβ40 fibrils compared to ThT. OPE2+ exhibited the largest fluorescence turn-on and highest sensitivity. Significantly, OPEs detected prefibrillar aggregates of Aβ42 and α-synuclein that ThT failed to detect. The superior sensing performance, the nonprotein specific detection, and the ability to selectively detect fibrillar and prefibrillar amyloid protein aggregates point to the potential of OPEs to overcome the limitations of existing probes and promise significant advancement in the detection of the myriad of protein aggregates involved in the early stages of AD and PD.

In the present study, we examined the inactivation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by synthetic conjugated polymers and oligomers developed in our laboratories as antimicrobials for bacteria, fungi, and nonenveloped viruses. The results show highly effective light-induced inactivation with several of these oligomers and polymers including irradiation with near-UV and visible light. In the best case, one oligomer induced a 5-log reduction in pfu/mL within 10 min. In general, the oligomers are more active than the polymers; however, the polymers are active with longer wavelength visible irradiation. Although not studied quantitatively, the results show that in the presence of the agents at concentrations similar to those used in the light studies, there is essentially no dark inactivation of the virus. Because three of the five materials/compounds examined are quaternary ammonium derivatives, this study indicates that conventional quaternary ammonium antimicrobials may not be active against SARS-CoV-2. Our results suggest several applications involving the incorporation of these materials in wipes, sprays, masks, and clothing and other personal protection equipment that can be useful in preventing infections and the spreading of this deadly virus and future outbreaks from similar viruses.

Developing new molecular ligands for the direct detection and tracking of amyloid protein aggregates is key to understanding and defeating myriad neurodegenerative and other disorders including Alzheimer’s and Parkinson’s diseases. A crucial factor in the performance of an amyloid dye is its ability to detect the amyloid structural motif independent of the sequence of the amyloid-forming protomer. The current study investigates structure–function relationships of a class of novel phenyleneethynylene (PPE)-based dyes and fluorescent polymers using amyloid fibrils formed by two model proteins: lysozyme and insulin. A small library of 18 PPE compounds that vary in molecular weights, charge densities, water solubilities, and types and geometries of functional groups was tested. One compound, the small anionic oligo(p-phenylene ethynylene) electrolyte OPE1, was identified as a selective sensor for the amyloid conformation of both lysozyme and insulin. On the basis of protein binding and photophysical changes observed in the dye from this set of PPE compounds, keys to the selective detection of the amyloid protein conformation include moderate size, negative charge, and substituents that provide high microenvironment sensitivity to the fluorescence yield. These principles can serve as a guide for the further refinement of the effective amyloid-sensing molecules.

Photodynamic therapy, in which malignant tissue is killed by targeted light exposure following administration of a photosensitizer, can be a valuable treatment modality but currently relies on passive transport and local irradiation to avoid off-target oxidation. We present a system of excited-state control for truly local delivery of singlet oxygen. An anionic phenylene ethynylene oligomer is initially quenched by water, producing minimal fluorescence and no measurable singlet oxygen generation. When presented with a binding partner, in this case an oppositely charged surfactant, changes in solvent microenvironment result in fluorescence unquenching, restoration of intersystem crossing to the triplet state, and singlet oxygen generation, as assayed by transient absorption spectroscopy and chemical trapping. This solvation-controlled photosensitizer model has possible applications as a theranostic agent for, for example, amyloid diseases.photosensitizer | self-assembly | conjugated oligomers | photodynamic therapy | excited states G eneration of reactive oxygen species as a product of photoexcited electronic states in organic molecules can be a useful tool in a variety of applications. The possibilities of spatially localized generation of reactive oxygen species (ROS) in response to irradiation are only just beginning to be explored, despite the more than 100-y history of phototherapy in modern medicine (1), and are already in the clinic in the form of photodynamic therapy (PDT) for cancers of the skin, esophagus, and organ linings, actinic keratosis, and acne (2, 3). Photodynamic destruction of pathogenic bacteria, viruses, and fungi is also under investigation for antibiowarfare applications, passive sanitization of hospital surfaces under room light, and active sanitization of medical devices such as catheters (4-8). A major drawback of systemically dosed PDT photosensitizers, which are primarily porphyrins or their prodrugs (9), is their accumulation in the skin and eyes leading to long-lasting (weeks to months) posttherapeutic photosensitivity (10). Generation of ROS outside the target area can have multiple deleterious effects by overwhelming endogenous ROS-dependent signaling cascades (11). A solution to these issues would be a localized photosensitizer whose ROS-generating properties can be controllably activated, for example, in response to the binding to a target.The motivation of the current study is to develop a tool for local delivery of singlet oxygen using binding and self-assemblymediated control of excited states. Under intra-or intercellular conditions, 99% of singlet oxygen cannot travel more than 300 nm from the site of its generation before it decays through the transfer of its electronic energy to vibrational modes of water (12); the presence of redox sites will reduce this effective distance further. This less than 300-nm radius, being less than a cellular length, indicates that an active photosensitizer in or at a target cell will have minimal effect on adjacent cells. Previous investiga...

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimer's disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-pphenylene ethynylenes (OPEs) exhibit selective binding and fluorescence turn-on in the presence of prefibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-β (Aβ) and αsynuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of Aβ fibrils and compared its efficacy to the well-known but nonselective photosensitizer methylene blue (MB). Our results show that, while MB photo-oxidized both monomeric and fibrillar conformers of Aβ40, OPE oxidized only Aβ40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed but retained the characteristic β-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPE's photosensitizing activity overcomes the limitation of off-target oxidation of traditional photosensitizers and represents an advancement of PDT as a viable strategy to treat neurodegenerative disorders.